Nature: ‘It’s all gone’: CAR-T therapy forces autoimmune diseases into remission

A study with dual CD19-BCMA CAR-T, for 13 SLE patients is published, with up to 46 months of follow-up. All patients are in remission besides P11 who received half of the dose (see the quote below)

It seems they have used much less chemotherapy,they mention only 300mg/m2, cyclophosphamide, and only the first 2 patients received any flu (there was no additional benefit it seems). So 3 x less chemo? or they've omitted to write 300 mg x 3 days?

Also, interesting (and scary) part:

Strange that even dsDNA came back, which never happened from what I know with German patients treated with only CD19, even.

Makes sense that the dual needs higher dose, though? Especially if chemo is 3x lower as well
.

Also, it's interesting that they measured IgA levels in saliva, which seem to come back at 8 months (not yet normal for everyone), and they did renal biopsy:

 

I doubt it. It might possibly be useful as part of a combination therapy but I have no idea with what.

 

From the recent report with dual BCMA CD19


Why would anti-SSA persist until 100+ days and then rapidly fall, what would be the explanation for this, if dual deleted every plasma cell, @Jonathan Edwards?

 

That looks like a calibration artefact to me. You have to be ever so careful about cross-calibrating these assays. Part of the problem is that the scale changes from 10 to 60 days per gradation. But there is something else odd going on. Antibody profiles after B depletion are always heterogeneous between patients. The right hand profiles are very similar but one time point shifted. That's odd.

It is conceivable that there is a biological mechanism that accelerates antibody depletion later but I don't think this is a question of deleting plasma cells - that would produce very early fall. I think plasma cells are dying from ageing after deep memory B cell depletion.

I also think one should be cautious about interpreting the zero line. There is no zero in an antibody assay. It is always a construct of calibration and a rather shaky one at that.

 

Hmm IgG went to "0" very fast so seems it can't be late plasma cells dying?!
Most patients were on 5g IVIG

 

That is a bit strange since it suggests that total IgG goes down quicker than autoantibody.
I think there may be an awful lot of uncertainty in these kinetic profiles. I don't like the way they have played around with the axes much.

It does look as if profound clearance of antibodies and presumably plasma cells occurs, by whatever means. That to me is the crucial experiment to do - to be prepared to get Ig levels very low. If it works then our original proposal will be validated after all. In other words you can break a B cell lineage cycle without killing T cells and get long term remission.

 

Well IASO Bio also has such graphs with even more clear IgG to near 0, with only BCMA.
But in their recent paper they mentioned something like "the persistence of CAR-T cells in autoimmune patients should be improved to keep an ongoing remission"
That got me thinking if someone relapsed from those 13 patients

 

They may assume that something else will bring back autoreactive B cells. Most immunologists do.
The problem with one or two relapses is that the clinical experiment is unlikely ever to be quite as clean as testing the theory needs. But if relapse is inevitable even with complete clearance of B lineage then we would have been wrong.

 

Dual cd19-bcma SLE researcher, from icellgene, told me to ask 6 months data when doing it...to be sure it's a reset...I guess whoever relapsed for now was within 6 months.
He was seeing significant number of relapses w only CD19. He is very against it.
But I wonder, for more less isolated LN, would still be logical to keep that as a first choice, despite ANA and some antibodies staying positive in some people.

 

I can't really follow what you are saying there.
6 months is much too short to judge reset. It is more like 5-8 years. Relapse with heavy duty immunoablation tends to come in over five years. With rituximab it continues for up to 8 years.

To be reasonably convinced of some resets I would like to see less than 40% relapse out at 5 years. A few relapses earlier may just mean that the regimen hasn't taken well for some cases.

 

I guess, he might mean that because I cant really wait and be untreated for 5 years, I should at least see 6 months data, to see I am not getting a really weak product that wont keep several years of remission (he was saying in a sense to buy myself few years and then repeat it if needed when better/more products available), because patients relapsed in less than 6m after some bad on€s, and I spoke to some of those patients who had a relapse in that time- like, I think 4 months, (in his published study there is a case of a very fast dsDNA return after getting to 'zero', they blame too low initial dose of CART).

I guess because B cell come back faster after CART than after monoclonal antibodies, the relapse when no reset occurred would be faster too!?

 

BCMA-CD19 bispecific CAR-T therapy in refractory chronic inflammatory demyelinating polyneuropathy

hope this means for SFN too

CAR T-Cell Therapy Seems Safe and Effective in CIDP
A new case report of bi-specific CAR T-cell therapy targeting BCMA and CD19 for treating chronic inflammatory demyelinating polyneuropathy (CIDP).

• 44-year-old male with recurrent numbness and weakness in the hands and feet.
• Side effects included fever and a transient increase in interleukin-6 levels managed with acetaminophen, mild cytokine release syndrome resolved within 2 weeks, and hypotension resolved after 2 weeks of bed rest and hydration.
• The patient's condition markedly improved, with almost complete muscle strength recovery by day 180 and restored walking ability.
• Post-treatment, he had no anti-GM4 or anti-GD3 antibodies and could discontinue all immunosuppressive agents without relapse.
• Initial treatments with intravenous immunoglobulin and high-dose pulse intravenous methylprednisolone improved symptoms but did not achieve complete remission.
• The researchers reported no other CAR-T cell therapy-related toxicities and noted this as the first reported case of CIDP treated with bispecific CAR-T therapy showing apparent efficacy.

full report>




https://www.sciencedirect.com/science/article/pii/S2949928324000440?fbclid=IwZXh0bgNhZW0CMTAAAR3dSGyK3EvShnK9r6v5RFYrzbsu3IZFyXvMRiYs_a-2K9eRQBi-ABOydeA_aem_AaNYgWO2UGpG_qFgp5NLEEnX-dMRsv2piP7BeK1U3ZUPXDPLClk-aNQ2jvfhoCtSo7GD_5khJ4ZT1KU3HNygobNJ#xd_co_f=MjQzMDFkZWEtYTllZi00YTcwLWE5YWItODVkMjlhYTFmMDg2~

 

Probably not. CIDP is a condition associated with clearly demonstrable autoantibodies if I remember rightly - I think IgM specifically. Small fibre neuropathy is not as far, as I know.

 

Pretty sure I found a study years ago where 60-70% of CIDP had SFN too, and that the same drugs are used (found effective?) like IVIG, cyclophosphamide, Vyvgart (?) and both SFN and/or CIDP co-occur with Sjogrens... , I'll keep my hope.

 

This one is also interesting :

A woman successfully became pregnant and gave birth to a daughter after CAR-T treatment for SLE
"Thanks to the advanced technology of the Municipal People's Hospital, becoming a mother successfully is the happiest thing for our whole family." On May 27, Xiao Du from Huangpu Town took her daughter to the Rheumatology and Immunology Department of the Municipal People's Hospital for a follow-up examination. When the doctor told her that all indicators were good and the child was relatively healthy, she was excited and burst into tears. It is understood that this is the first case of a systemic lupus erythematosus (SLE) patient in our city who recovered after chimeric antigen receptor T cells (CAR-T cells) treatment and successfully became pregnant and gave birth to a healthy baby. It is also the first successful case of childbirth after CAR-T treatment in the world.
https://www.zsnews.cn/health/index/...cARiKfkreSEg44WGMCg9-abxZYclEMaC02QnorOBjx_HW

 

and this especially:
First case report from China with donor (allogeneic) off the shelf CAR-T cells
lower chemo dose used
her disease activity score - SLEDAI went from 18 to 0
After a series of rigorous examinations and evaluations, Li Ting was selected to participate in the clinical trial. The experimental drug that Li Ting participated in fully transformed allogeneic immune cells through gene editing technology, effectively avoiding the risks of GVHD (graft-versus-host disease) and HVG (transplant rejection) that may exist in allogeneic cell transplantation. Compared with autologous CAR-T, this clinical study uses healthy donor blood samples for production, does not require the collection of autologous cells in advance, and can be used immediately. It has a definite clinical efficacy and high safety. At the same time, because the dose of lymphocyte-clearing chemotherapy (lymphocyte clearance) is lower than that of autologous CAR-T, the possible clinical risks are further reduced.When universal CAR-T cells were infused into Li Ting's body, something magical happened. Her physical condition began to improve significantly, and there were no serious adverse reactions such as infection. Her hair loss, erythema, edema, urine protein, hematuria, and joint pain improved significantly, and the systemic lupus erythematosus score dropped from 18 points before treatment to 0 points, and she gradually stopped all hormones and immunosuppressants.
https://mp.weixin.qq.com/s/HNSUD4-3pF3vvWtvi5K9Z

 

Reminds me of the cases we treated with rituximab 25 years ago!!

 

and now almost nobody wants rituximab, so easy to get it . Will it take 25 years so nobody wants CAR-T so I can finally access it?

 

https://www.medpagetoday.com/meetingcoverage/eular/110610

CAR-T Treatment Continues to Astonish in Rheumatologic Diseases